This proposal consists of three unrelated synthetic projects designed to prepare structurally novel, biologically active natural products of potential interest as drugs. In thee first project, the cytotoxic guanidinium alkaloid ptilomycalin A will be prepared. Ptilomycalin A, isolated from the Caribbean sponge Ptilocaulis spiculifer in 1989, is a potent cytotoxin and shows antifungal, antiviral and antimicrobial activity. The related crambescidins, which show similar biological activity, were isolated by Rinehart in 1991 from the Mediterranean sponge Crambe crambe. Biologically less interesting crambines A and B were isolated from the same sponge in 1990. The biological activity and structural novelty of ptilomycalin A and the crambescidins make these significant synthetic targets. Based on our synthesis of ptilocaulin, which was also isolated from Ptilocaulis spiculifer, a route to ptilomycalin A based on the one-pot addition of guanidine to an acyclic precursor to form the five rings of ptilomycalin A in a single step has been developed. Model studies leading the to the bicyclic guanidine moieties of crambines A and B have been completed and published and a model study leading to the three central rings of ptilomycalin A has been completed. The three specific aims in this area are: (1) Synthesis of the pentacyclic portion of ptilomycalin A as the methyl ester.(2) Synthesis of crambines A and B. (3) Synthesis of ptilomycalin A with the complete side chain. The second project is the synthesis of pyridoxatin, a structurally novel, potent free-radical scavenger isolated from a fungus culture, which may be of therapeutic interest. The third project is the synthesis of phloeodictine A, a structurally novel, amidinium antimicrobial and cytotoxic agent recently isolated from a deep water sponge. An efficient route to phloeodictine A that builds on chemistry discovered in the synthesis of the pyrantel series of anthelmintics is being examined.